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二酮酸类化合物(DKAs)是目前最有前景的HIV-1整合酶(integrase,IN)抑制剂.为了解DKAs引起的多种耐药株共有的耐药性机理,选择3种S-1360引起的IN耐药突变体,用分子对接和分子动力学模拟,研究了野生型和突变型IN与S-1360的结合模式,基于该结合模式探讨了3种耐药突变体所共有的耐药性机理.结果表明:在突变体中,S-1360结合到耐药突变IN核心区中的位置靠近功能loop 3区却远离与DNA结合的关键残基,结合位置不同导致S-1360的抑制作用部分丧失;残基138到166区域的柔性对IN发挥生物学功能很重要,S-1360能与DNA结合的关键残基N155及K159形成氢键,这2个氢键作用降低了该区域的柔性,突变体中无类似氢键,因而该区域柔性增高;在突变体中,S-1360的苯环远离病毒DNA结合区,不能阻止病毒DNA末端暴露给宿主DNA;T66I突变导致残基Ⅰ的长侧链占据IN的活性口袋,阻止抑制剂以与野生型中相同的方式结合到活性中心,这均是产生抗药性的重要原因.这些模拟结果与实验结果吻合,可为抗IN的抑制剂设计和改造提供帮助.
Diketone compounds (DKAs) are currently the most promising inhibitors of HIV-1 integrase (IN) .In order to understand the common resistance mechanism of DKAs to multiple drug-resistant strains, three S-1360 Induced IN-resistant mutants, the mode of binding of wild-type and mutant IN and S-1360 was studied by molecular docking and molecular dynamics simulation, and the resistance shared by the three kinds of resistant mutants was discussed based on the binding mode The results showed that S-1360 binds to the core region of drug-resistant mutant IN in a close proximity to the functional loop 3 region but far away from the key residues that bind to DNA, resulting in the inhibition of S-1360 by different binding sites Partially lost; flexibility of residues 138-166 region is important for IN to play a biological role, S-1360 can form hydrogen bonds with key residues N155 and K159 of DNA binding, which reduce the flexibility of the region In the mutant, the benzene ring of S-1360 was far away from the viral DNA binding region and could not prevent the end of the viral DNA from being exposed to the host DNA. The mutation of T66I led to the prolongation of the residue I Side chains occupy the active pocket of IN, blocking the inhibitor to the same side as in the wild type Binding to the active site, which are important reasons for drug resistance.These results are in good agreement with the experimental results, which can be helpful for the design and modification of anti-IN inhibitors.